The use of recombinant proteins and other large molecules for diagnosis and therapy has been one of the greatest achievements of biotechnology. According to some reports, nearly 20 recombinant human protein pharmaceuticals have been approved for clinical use. Porter, S., Journal of Pharmaceutical Sciences 90(1):1-11 (2001). Biological medicinal products and therapeutic agents have become a growing proportion of tested pharmaceutical drugs.
Even with the demonstrated success of recombinant proteins, antibodies and other large molecules in therapeutic and diagnostic applications, there has been a concern that the delivery of pharmacological proteins to individuals would induce an immune response, especially when the protein is provided in multiple doses over a period of time. Koren, et al., Current Pharmaceutical Biotechnology 3(4):349-360 (2002) present a table (table 1 at p. 352-3) detailing the incidence and clinical sequelae of antibody responses to some therapeutic proteins. Porter, supra, also provides a summary of the actual reported observations regarding human immune response to administered doses of recombinant human proteins.
Three categories of immune reactions have been reviewed in Rosenberg, A. S., Immunogenicity of Therapeutic Biological Products, Dev. Biol. Basel 112, pp. 15-212 (2003).
A first type of immune reaction, immediate hypersensitivity responses that may cause anaphylactic or anaphylactoid responses, has presented the greatest concern. This type of immune reaction is rare, however. It has most frequently been linked to recurrent administration of bacterial proteins which lack a mammalian counterpart. Id.
A second type of immune reaction is characterized by the formation of antibodies that neutralize not only the therapeutic agent but also endogenous factors. Thus, this type of immune reaction has the potential of causing serious adverse consequences. Rosenberg, supra.
Lastly, there has been the concern that the generation of binding antibodies may cause invasion reactions, alter pharmacokinetics and biodistribution, and potentially diminish product efficacy. For example, antibodies to primatized, chimeric or humanized antibody therapeutics like infleximab, retuximab, and the like, have been observed in patients.
Several factors may impact the generation of immune responses to therapeutic proteins (particularly the non-self portion of a therapeutic protein), including the immunogenicity of recombinant proteins, the presence of impurities, product aggregation, dose, route and frequency of administration. Rosenberg supra.
Cytokines are one of the classes of proteins whose use as therapeutic agents have encountered safety and efficacy issues due to their actual and potential immunogenicity. Reviewed in Herzyk, D. J., Current Opinion in Molecular Therapeutics 5(2):167-171 (2003).
Antibodies, diabodies, and other such immunoglobulin-like molecules used for imaging and therapy have also encountered issues with actual and potential immunogenicity.
Several approaches have been advanced with varying success in an effort to decrease the immunogenicity of immunogenic therapeutic molecules, many of which involve further manipulations of the therapeutic molecule. Such approaches include de-immunization, Issacs, J D, Rheumatology 40:724-738 (2001), gene-shuffling, Kurtzman, et al., Curr Opin Biotechnol 12:361-370 (2001); Chang, et al., Nat Biotechnol 17:793-797 (1999), pegylation, Rosemberg, et al., J App Physiol 91:2213-2223 (2001); Tsutsumi, et al., Proc Natl Acad Sci 97:8548-8553 (2000), and producing IgG molecules having a human sequence in transgenic mice, Davis, et al., Cancer and Metastasis Reviews 18:421-425 (1999); Green, et al., J Immunol Meth 231:11-23 (1999). Such approaches are most likely to be successful at reducing an immunogenic response when the mechanism by which the therapeutic molecule induces the response is known. Even if successful, the approaches will involve considerable delay in the development and approval of a therapeutic molecule for use in humans.
Accordingly, there is a need for safe and effective compositions and methods to decrease the probability of incidence of an immune reaction to immunogenic therapeutic molecules, and to decrease antibody production when said immune reactions do occur.